Recent studies have established the existence of a nonadrenergic noncholinergic inhibitory nervous system (NANCIS) in airways. The NANCIS appears to be the principal inhibitory nervous input to human airways. The functional significance of this nervous system and its role in pathophysiology of human airways disease are unknown. Also unknown is the identity of its neurotransmitter, although evidence suggests it is a neuropeptide. Little is known about the system's basic pharmacological characteristics and there is no information on biochemical mechanisms associated with termination of transmitter action or signal transduction mechanisms used by the system to relax airways. Studies outlined in this proposal will use physiologic, pharmacologic and biochemical approaches to: (i) assess the functional significance of the lung NANCIS; (ii) characterize the system with regard to its modulation by other neurotransmitters or hormones and determine whether it modulates release of other mediators; (iii) demonstrate release and characterize the nature of the NANCIS neurotransmitter; (iv) identify and characterize peptidases in airways that degrade neuropeptides and the NANCIS transmitter; (v) determine signal transduction mechanisms used by the NANCIS to relax airway smooth muscle; and (vi) develop cell lines of intrinsic airway neurons to aid in the investigation of the lung NANCIS. By achieving these aims, this research could provide new insight into physiologic mechanisms regulating airway caliber, pathophysiologic mechanisms underlying airways hyperreactivity and cellular events that control nerve-mediated bronchodilation.